Our long-term goal is to delineate the underlying molecular mechanisms and physiological significance of the maintenance of endoplasmic reticulum (ER) homeostasis by three key quality-control systems, ERassociated degradation (ERAD), autophagy and unfolded protein response (UPR). Although recent studies have implied a possible role of UPR in the pathogenesis of obesity and type-2 diabetes, the maintenance and physiological significance of ER homeostasis in adipocytes remains enigma. Our recent data demonstrate that Sel1L, a key adaptor protein for the E3 ligase Hrd1 in mammalian ERAD, plays a critical role in adipocytes and metabolic regulation. Adipocyte-specific Sel1L-deficient mice (Sel1L?adipo) are protected against diet-induced obesity with elevated UPR and autophagy, but uncoupled from inflammation and cell death in WAT. Moreover, our data demonstrate a critical requirement of Sel1L for the secretion of lipoprotein lipase (LPL), which may account for postprandial hypertriglyceridemia of Sel1L?adipo mice. Thus, our data point to an indispensable role of Sel1L in adipocyte function in the pathogenesis of obesity. However, underlying molecular mechanism(s) by which Sel1L affects adipocyte function and obesity remain largely unclear. We hypothesize that Sel1L regulates adipocyte function and metabolism via both Hrd1/ERAD-dependent and -independent mechanisms, and via the crosstalk among three ER qualitycontrol systems (Sel1L-Hrd1 ERAD, UPR and autophagy) in adipocytes. Using an array of adipocytespecific knockout mouse models coupled with in vitro mechanistic studies, we will determine mechanistically how Se1L regulates adipocyte function and metabolism with a particular emphasis on Hrd1/ERAD dependency in Aim 1 and on the crosstalk among three ER quality-control systems in adipocytes in Aim 2. The generation and characterization of several adipocyte-specific double knockout mouse models with various levels of ER stress will elucidate not only the functional crosstalk among key ER quality-control machineries, but also the cellular and pathological consequences of perturbed ER homeostasis in the pathogenesis of obesity and type-2 diabetes. Finally, this study may identify a novel endogenous substrate of the Sel1L-Hrd1 ERAD complex and establish a novel mechanism underlying a feedback regulatory loop between Sel1L-Hrd1 ERAD and IRE1??signaling. RELEVANCE TO HUMAN HEALTH: Protein misfolding is detrimental to the cell and has been linked to the pathogenesis of several human diseases. Despite nearly a decade of effort, the role of ER homeostasis in adipocytes in the pathogenesis of obesity remains vague. Our preliminary data point to adipocyte Sel1L as a key regulator in ER homeostasis and metabolism. A successful completion of this study will have a powerful impact on our understanding of the physiological significance of ER quality-control systems and the maintenance of ER homeostasis in adipocytes in the context of diet-induced obesity.